The present invention relates to the identification of the RPE65 gene in dogs, identification of a mutation in the RPE65 gene in the briard breed of dogs, a method for identifying dogs that are genetically normal, are carriers of, or are affected with congenital stationary night blindness by detecting the presence of the mutation, and a method of selecting dogs for breeding.
The briard dog is affected with a recessively inherited retinal disorder characterized by congenital night blindness with various degrees of visual impairment under photopic illumination. Vision in affected dogs ranges from normal day vision to profound day blindness (Narfstrxc3x6m et al., xe2x80x9cHereditary Retinal Dystrophy In The Briard Dog: Clinical And Hereditary Characteristics,xe2x80x9d Veterinary and Comparative Ophthalmology, 4:85-92 (1994)). The disease was initially described in Swedish dogs as a stationary disorder analogous to human congenital stationary night blindness (CSNB; Narfstrxc3x6m et al., xe2x80x9cHereditary Retinal Dystrophy In The Briard Dog: Clinical And Hereditary Characteristics,xe2x80x9d Veterinary and Comparative Ophthalmology, 4:85-92 (1994)). More recently, the disease has been described as having a progressive component, and has been termed hereditary retinal dystrophy (Wrigstad et al., xe2x80x9cSlowly Progressive Changes Of The Retina And Retinal Pigments Epithelium In Briard Dogs With Hereditary Retinal Dystrophy. A Morphologic Study,xe2x80x9d Doc. Ophthalmol., 87:337-354 (1994); Wrigstad, xe2x80x9cHereditary Dystrophy Of The Retina And The Retinal Pigment Epithelium In A Strain Of Briard Dogs: A Clinical, Morphologic And Electroretinographic Study,xe2x80x9d Linkxc3x6ping University Medical Dissertation #423 (1994)). Along with the visual impairment, affected dogs have an abnormal electroretinogram (ERG); in general, the recorded responses are normal in waveform, but show a marked diminution of response amplitudes, similar to a xe2x80x9cRiggs typexe2x80x9d ERG in man. The ERG recorded under DC conditions shows complete absence of the a-, b-, and c-waves, with the latter waveform being replaced by a very slow negative potential which develops when the stimulus intensity is greater than 3 log units above the normal b-wave threshold. The abnormalities in the a- and b-waves can be interpreted as representing a delay in rod phototransduction (Nilsson et al., xe2x80x9cChanges In The DC Electroretinogram In Briard Dogs With Hereditary Congenital Night Blindness And Partial Day Blindness,xe2x80x9d Exp. Eye Res., 54:291-296 (1992)). A similar disease is also recognized in other countries, e.g. France, Canada, and the United States. In the United States, the disease is termed congenital stationary nightblindness, and csnb has been designated as the gene symbol for the disease locus. Apart from the above studies in Swedish briard dogs, no other systematic investigation of the disease has been reported, nor has there been definitive proof that csnb and retinal dystrophy represent the same disorder.
The present invention is directed to overcoming the above-noted deficiencies in the prior art.
The present invention relates to an isolated nucleic acid molecule encoding canine RPE65.
The present invention also relates to an isolated nucleic acid molecule encoding canine RPE65 having a mutation in one or both alleles indicative of a carrier of or a dog affected with congenital stationary night blindness.
The present invention also relates to a method for identifying dogs which are genetically normal, are carriers of, or are affected with congenital stationary night blindness, said method including obtaining a biological sample from a dog and testing the biological sample for a gene encoding canine RPE65 having a nucleic acid mutation in one or both alleles indicative of a carrier of or a dog affected with congenital stationary night blindness.
Another aspect of the present invention is a method for selecting dogs for breeding which includes obtaining a biological sample from a dog, testing the biological sample for a gene encoding canine RPE65 having a nucleic acid mutation in one or both alleles indicative of a carrier of or a dog affected with congenital stationary night blindness, and eliminating dogs with the mutation from a breeding stock or breeding the dogs with the mutation with genetically normal dogs.
Yet another aspect of the present invention is an isolated nucleic acid molecule including a DNA molecule having the nucleotide sequence selected from the group consisting of SEQ. ID. No. 4, SEQ. ID. No. 5, SEQ. ID. No. 6, SEQ. ID. No. 7, and SEQ. ID. No. 8.
The present invention has enabled a DNA-based diagnostic test for congenital stationary night blindness to be developed, and, therefore, animals suitable for breeding can be identified. In particular, identifying carriers for congenital stationary night blindness through the identification of the AAGA deletion mutation at nucleotides 487-490 in a gene encoding canine RPE65 allows a breeder to eliminate the carriers from the breeding stock or breed carriers with genetically normal dogs.